Semipinacol rearrangements forming 1-azaspirocycles as well as a formal synthesis of fasicularin are reported. 1-Azaspirocycles are formed by either an acid mediated semipinacol rearrangement or an epoxide semipinacol rearrangement. Semipinacol rearrangement substrates are prepared from N-para-toluenesulfonyl protected lactams. 1-Azaspiro[5.4]decanones (a) are formed in high yield and moderate to excellent diastereoselectivity via acid mediated semipinacol rearrangement of substrates resembling

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... b. Unfortunately, larger cyclic systems (such as c) are not formed using this method due to competing hydrolysis. The epoxide semipinacol rearrangement offers a viable solution to the hydrolysis problem. 1-Azaspiro[5.5]undecanones (d) are formed in excellent yield and diastereoselectivity from substrates resembling e. Currently, the restricted scope of this method remains a drawback. The epoxide semipinacol rearrangement of substrates resembling f affords 1-azaspiro[5.4]decanones (g) in good diastereoselectivity provided ytterbium (III) triflate is employed as the Lewis acid. Complementary diastereomer formation (h) is possible upon substituting the trimethylsilyl protecting group in the substrate (such as in i) and the ytterbium (III) Lewis acid for titanium (IV) tetrachloride. The highest level of diastereoselectivity in the epoxide semipinacol rearrangement is obtained when no protecting group is employed (i.e. j). This method, however, is not yet general. The formal synthesis of fasicularin was achieved in 24 steps (longest linear sequence) starting from inexpensive L-glutamic acid. The spiro centre is established by use of the semipinacol rearrangement methodology developed in our laboratory. Other key features of the synthesis include a S-alkyl Suzuki-Miyaura coupling followed by a Mitsunobu-type ring closure to assemble the A-ring and a substrate-controlled hydrogenation to establish the A-B trans ring fusion. Significantly, all stereocentres but one are established by stereochemical relay of the stereochemistry pre [...]